This invention relates to synthesis of an alkaloid which is active against lymphocytic leukemia in test mice. It further relates to the synthesis of deoxyharringtonine and its precursor 3'-O-(5-methyl-2-oxohexanoyl)-cephalotaxine.
Among the alkaloids which have been isolated from Cephalotaxus harringtonia plant material are cephalotaxine and a number of its esters [Powell, Weisleder, Smith, and Wolff, Tetrahedron Lett. 4081 (1969); Powell, Weisleder, Smith, and Rohwedder, Tetrahedron Lett. 815 (1970); and Mikolajczak et al., Tetrahedron 28: 1995 (1972)]. Some of these esters, which are derived from relatively complex dicarboxylic acid moieties have been found to exhibit significant antitumor activity in the P388 system [cephalotaxine itself is inactive; Powell et al., J. Pharm. Sci. 61: 1227 (1972)]. Two of the esters have been approved for the preclinical phase of pharmacological evaluation at the National Cancer Institute. Continued biological testing of the active esters requires quantities which cannot be supplied by natural sources. The partial synthesis of these esters from natural and synthetic cephalotaxine which is available in considerably larger quantities is very desirable. We have discovered a successful conversion of cephalotaxine to one of its active naturally occurring esters, deoxyharringtonine.